Highly potent and selective degrader targeting ERα to improve the treatment outcomes of breast cancer

Estrogen receptor alpha (ERα) is overexpressed in approximately 70 % of breast Cancer cases; therefore, it is considered a primary therapeutic target for breast Cancer. Several therapeutic agents, including selective Estrogen receptor modulators, aromatase inhibitors, selective Estrogen receptor degraders, and proteolysis-targeting chimeras (PROTACs), have been developed to antagonize and degrade ERα. The representative ERα-targeting PROTAC (ERα-PROTAC) agent ARV-471 has been used to treat locally advanced or metastatic breast Cancer in clinical trials. Herein, we designed, synthesized, and evaluated several novel ERα-PROTAC agents. After systematic structural optimization, compound A16 was found to have excellent antiproliferative and ERα-inhibitory activities in the breast Cancer cell line MCF-7. A16 selectively degraded ERα (DC₅₀ = 3.78 nM) through the ubiquitin-proteasome pathway in a time- and concentration-dependent manner. It effectively attenuated drug resistance (MCF-7 Y537S cells; IC₅₀ = 1.3 nM), inhibited proliferation, and induced Apoptosis in MCF-7 cells. In addition, it exhibited excellent antitumor effects (10 mg/kg/d intraperitoneal injection; total growth inhibition = 80.11 %) and a good safety profile in an MCF-7 xenograft model, highlighting its potential as a novel drug candidate for breast Cancer.